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Diabetic foot (DF) is the destruction of the skin and deep tissues (including muscle and bone) at the distal end of the ankle in diabetic patients, often associated with infection and arterial occlusion of the lower extremities. DF is one of the main causes of disability and death in diabetic patients. Its recurrence rate and medical expenses are both high, and it ranks tenth among the diseases that cause a heavy burden on patients and society in the world. Diabetic foot ulcer (DFU) is the most common manifestation of DF and the main cause of amputation in diabetic patients. Globally, 3 diabetic patients are amputated or amputated due to foot ulcers every minute.

At present, the main treatments for diabetic foot ulcers focus on evening dressings, negative pressure, electrical stimulation, hyperbaric oxygen, and skin transplantation, but the therapeutic effects are often not satisfactory. The annual increase in amputations also means that DFU treatment methods are in urgent need of improvement.

Targeting the macrophage phenotype may be a potentially effective treatment for DFU

DFU is pathologically complex, mainly because the ulcer is damaged by a variety of risk factors, such as poor compliance with treatment, the severity of the ulcer, the location and duration of the ulcer, vascular conditions, and the level of glycosylated hemoglobin (HbA1c) Control, smoking habits and renal dysfunction. These factors make the clinical urgent need for new effective interventions to deal with this life-threatening disease.

Increasing scientific evidence suggests that targeting the macrophage phenotype may be a potentially effective treatment for DFU, because hyperglycemia increases the ratio of pro-inflammatory M1 macrophages to pro-regenerative M2 macrophages. ON101 exerts its therapeutic effect by regulating the balance between M1 and M2 macrophages.

 

ON101 has obvious therapeutic potential in promoting wound healing

ON101 is composed of two active pharmaceutical ingredients: PA-F4 of Eryngium japonicus extract and S1 of Centella asiatica extract. Many literatures show that these two medicinal materials have significant pharmacological activity on wound healing. The 48 pharmacological studies of ON101 have shown that the synergistic effect of these two raw materials helps to regulate the ratio of M1/M2 macrophages. On the one hand, PA-F4, by inhibiting the NLRP3-mediated inflammasome information pathway and inhibiting the production of downstream inflammatory cytokines such as interleukin (IL)-1β and IL-6 in the inflammatory phase, significantly reduces the production of M1 macrophages. Activity; on the other hand, S1 activates M2 macrophages by increasing collagen synthesis, stimulating fibroblast proliferation and keratinocyte migration, which further proves that ON101 is in the db/db mouse model of diabetes, obesity and dyslipidemia It can effectively accelerate wound healing and change the ulcer state from an inflammatory period to a proliferation and remodeling period.

A clinical pharmacokinetic study of 12 patients with DFU showed that the maximum body concentration of ON101 was similar on day 1 and day 14 in single and repeated doses twice a day, indicating that the drug is in the body There was no significant accumulation, and no treatment-related adverse events were observed.

In a clinical trial of 24 patients with Wagner grade 3 chronic DFU, after 2 weeks of treatment with ON101, the wound size was reduced by about 20%, and there were no serious adverse events. Among 21 evaluable patients, the average wound size at baseline was 359 mm2 (range 20-2352 mm2), which decreased to 293 mm2 after 2 weeks of medical treatment.

In another clinical trial, 30 Wagner grade 1 chronic DFU were treated with ON101 for up to 12 weeks, and the final cure rate was 50%. The average wound area at baseline was 577 (range, 303-1225) mm2, which decreased to 163 mm2 after 12 weeks of ON101 treatment. In summary, ON101 has obvious therapeutic potential in promoting wound healing.

 

Experiment method

This multi-center, evaluator-blinded, phase 3 randomized clinical trial was conducted at 21 medical/clinical centers in the United States, China, and Taiwan from November 23, 2012 to May 11, 2020.

Intervention measures: the test group applied ON101 twice a day, and the control group changed the hydrophilic fiber dressing once a day or 2-3 times a week. The 16-week treatment period ended and the follow-up was 12 weeks.

The primary efficacy endpoint is the complete wound healing rate (complete healing refers to the complete epithelialization of the wound during 2 consecutive visits during the treatment period), which is evaluated based on the full analysis set (FAS) of all participants and data collected after randomization. The safety endpoint evaluation includes the evaluation of the incidence of adverse events, clinical laboratory values ​​and vital signs.

There were 236 patients in FAS (175 males (74.1%); mean age 57 ± 10.9 years), 184 (78%) were Wagner grade 2 ulcers, 117 (49.6%) were plantar ulcers, and 64 (27.1) %) baseline HbA1c ≥ 9%. The average ulcer size was 4.8 cm2 (SD 4.41), and the average duration of the target ulcer before enrollment was 7.15 months.

The average HbA1c at baseline was 8.1% (SD 1.63), and there was no significant change at the end of treatment (the average HbA1c in the ON101 group was 8% and the control group was 7.9%), and the time to diagnose diabetes in 144 patients (61%) was> 10 years . The FAS patients were randomly assigned 1:1: 114 cases (48.3%) in the hydrophilic fiber dressing group, 122 cases (51.7%) in the ON101 group, and the treatment time was 16 weeks. 16 patients (13.1%) in the ON101 group and 21 patients (18.40%) in the hydrophilic fiber dressing group terminated the study early (total 37 cases)

The main efficacy results showed that 74 patients (60.7%) in the ON101 group and 40 patients (35.1%) in the hydrophilic fiber dressing group achieved wound closure within 16 weeks (OR: 2.84; 95% CI: 1.66–4.84; P =.0001). Similar results were observed in the modified intention-to-treat (mITT). 61.9% (73/118) of the patients in the ON101 group and 33.9% (38/112) of the control group had closed ulcers (OR: 3.15; 95% CI: 1.82–5.43; P <.0001). The degree of wound closure was evaluated by an independent evaluator.

 

Test Conclusions

In this multicenter randomized clinical trial, ON101 showed a better therapeutic effect than hydrophilic fiber dressings in the treatment of DFUs, and showed consistent efficacy in all patients, including DFU-related risk factors (glycated hemoglobin Level, ≥9%; ulcer area,> 5 cm2 and duration of DFU, ≥ 6 months).

ON101 has an excellent effect of promoting the complete healing of DFU. Hyperglycemia is the source of chronic DFU, which delays the transformation of M1-M2 macrophages and prolongs the inflammation period. ON101 can restore the balance of M1/M2 macrophage imbalance caused by hyperglycemia, promote M1-M2 transformation, and accelerate the healing of ulcer wounds. It can not only treat new ulcers, but also treat high-risk ulcers, including ulcers that last longer than 6 Months, ulcer size> 5cm2 and HbA1c> 9% showed the robust efficacy of ON101. During the 16-week treatment period, the complete wound healing rate (35.1%) of the hydrophilic fiber dressing in the control group was consistent with the trend of a 12-week intention-to-treat analysis by Jeffcoate et al. (28.2%) in the previous trial. This means that the design and execution of this trial are consistent with other randomized controlled trials. ON101 can be used after debridement, self-administered at home, and its convenience is the same as the hydrophilic fiber dressing reference.

The field of DFU has always lacked ideal drug treatment, and related research progress has been quite slow. ON101, as a new drug used in DFU treatment, is expected to bring new hope to DFU patients!

 

Reference

[1] Huang Y, Lin C, Cheng N, et al. Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(9):e2122607 . doi:10.1001/jamanetworkopen.2021.22607

[3] Zhou Gang, Li Haihong, Fu Xiaobing. Research status of diabetic foot ulcers[J]. Chinese Tissue Engineering Research, 2004, 8(033):7540-7541.

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